The diagnosis of 15,000 new cases of HIV infections every day demonstrates the pressing need for a prophylactic HIV vaccine to prevent further spread of the pandemic. Some of the most encouraging results have been achieved with viral vector-based vaccines coding for multivalent HIV immunogens. High transduction efficiency of many cell types including dendritic cells as well as in vivo production of immunogens in transduced cells mimic a natural infection without the associated health risks and contribute to the overall efficacy of viral vectors. Since each vector system has certain limitations such as strong anti-vector responses (adeno-, poxviral vectors), limited capacity (AAV), transduction of replicating cells only (retroviral vector) or insertion into the host genome (retro-, lentiviral vectors), we propose to explore a novel non-integrating lentiviral vector based on Feline Immunodeficiency Virus (FIV) which can address these shortcomings of the current vector. So far, the development of lentiviral vectors for HIV vaccines has been hampered by concerns of insertional mutagenesis and general safety for HIV-derived lentiviral vector systems. The proposed FIV vector does not cause disease in humans and does not integrate (FIVdeltaIN), thus avoiding both issues. To date, neither the standard FIV vector nor its integration-deficient version (FIVdeltaIN) have been explored for HIV vaccines. This novel concept combines high transduction efficiency, large payload, weak anti-vector responses allowing repeat vaccinations and the improved safety profile of the feline FIVdeltaIN vector (abolished integration). Here, we propose a proof-of-concept study to demonstrate that non-integrating FIV vectors are capable of inducing immune responses to encoded antigens while avoiding strong anti-vector responses. This hypothesis is based on recent data indicating that genes delivered by integration-deficient lentiviral vectors may be expressed for several days. Additional studies are aimed at investigating humoral and cellular short-term and memory anti-HIV responses of an FIVdeltalN-based HIV vaccine delivering a multivalent HIV-1 immunogen coding for gag, pol, tat and rev. Importantly, adaptive and innate immune responses to the FIVdeltaIN vector will be monitored. In summary, we propose to combine several desirable characteristics within 1 novel viral vector-based delivery system in an effort to address shortcomings of previously described delivery systems for HIV vaccines. [unreadable] [unreadable] [unreadable]